Experimental therapeutic approaches for androgen-resistant prostate cancer are actively investigated. It is known that modified oligonucleotides bearing STAT3 binding sequences induced apoptosis in DU-145 and other androgen-insensitive prostate cancer cell lines and retarded the in vivo growth of DU-145 cells in a xenograft model. Such inhibitors are attractive in theory but lack a practical method for delivery in the clinical setting. One possible approach to overcome this roadblock is to use peptide-mediated transport, thereby coupling a cell-penetrating peptide (CPP) to an anti-STAT3 therapeutic payload. An inherent advantage of using CPPs is the ability to design cell specificity in the sequence, as well as target organelle specificity through inclusion of nuclear localization signals (NLS).
CPPs for prostate cancer have been examined in conjunction with delivery of therapeutic payloads including methotrexate-loaded liposomes, double-stranded decoys, and radioactive gadolinium complexes targeted to c-myc. The NLS of several transcription factors were compared in various tumor types with varying degrees of efficacy with regard to uptake and nuclear localization. As for delivery of an oligonucleotide payload, one study using CPPs consisting of cell surface ligands linked to NLS and conjugated to peptide nucleic acids (PNAs) found optimal efficacy under serum-free conditions at 5 mM, a concentration that is not commercially feasible due to prohibitive costs. Clearly, more studies on optimizing CPPs for delivery of therapeutic oligonucleotide or PNA payloads are needed in order to bring new therapeutic entities to the clinic.